Synthesis and Biological Activities of the Optical Isomers of (±)-4-Amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]benzamide (Mosapride)

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The enantiomers, (S)-(-)-1 and (R)-(+)-1,of (±)-4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholinyl]methyl]benzamide (mosapride) [(±)-1], a new and selective gastroprokinetic agent, were prepared from optically active [4-(4-fluorobenzyl)-2-morpholinyl]methylamines (S)-(-)-4 and (R)-(+)-4,respectively. The requisite (S)-(-)-4 and (R)-(+)-4 were prepared by optical resolution of [4-(4-fluorobenzyl)-2-morpholinyl]methyl p-toluenesulfonate [(±)-5] using (-)- and (+)-N-(p-toluenesulfonyl)glutamic acids, followed by amination of the tosyloxy groups of (R)-(-)-5 and (S)-(+)-5,respectively. The absolute configurations of (R)-(-)-5 and (S)-(+)-5 were determined on the basis of an asymmetric synthesis of (R)-(-)-5 from (S)-(+)-benzyl glycidyl ether [(S)-(+)-11]. Mosapride and its enantiomers, (S)-(-)-1 and (R)-(+)-1,were essentially equipotent in serotonin 5-HT_4 receptor agonistic activity on the electrically evoked contractions in isolated guinea pig ileum.
社団法人日本薬学会の論文
1994-04-15